The long-term goal of these studies is to develop therapeutic strategies to treat or prevent breast cancer. Since our demonstration that the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed and functionally active in breast cancer cells, a rapidly growing body of evidence has accumulated indicating that PPARgamma plays a central role in many types of cancer including breast cancer. Ligands include the antidiabetic thiazolidinediones, prostaglandin J2, fatty acids, and others. Treating breast cancer cells with PPARgamma ligands have alternatively been reported to induce cell cycle withdrawal, apoptosis, or mediate the expression of genes leading to a more differentiated, less malignant state. Other ligands, including fatty acids, have been reported to mediate the expression of genes that alter the malignancy and metastatic potential of breast cancer cells. The mechanism underlying these divergent actions has not been established. We have recently reported that the expression of ERalpha inhibits PPARgamma transactivation. Thus we will test the hypothesis that selective transactivation of PPARgamma by different ligands mediates gene expression profiles that favor either differentiation or proliferation, depending on the specific ligand used and the functional status of the ER in the same cells. Therefore, in Specific Aim 1 we will test the hypothesis that different PPARgamma ligands induce conformational changes that result in selective regulation of gene expression profiles and physiological responses in normal epithelia and in breast cancer cells. In Specific Aim 2 we will examine the necessity of PPARgamma in mediating the gene expression profiles involved in proliferation, differentiation, and apoptosis. In Specific Aim 3, we will examine the mechanism whereby the estrogen receptor alters the transactivation of PPARgamma and examine the physiological consequences of this interaction. This represents a novel approach to understanding the role PPARy plays in breast cancer and its selective modulation could point to novel mechanisms of action and to therapeutic targets.